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      Association analysis of ANK3 gene variants with schizophrenia in a northern Chinese Han population

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          Abstract

          Schizophrenia is a chronic, severely debilitating mental disorder. Many studies have suggested that genetic factors play an important role in the onset and development of schizophrenia. In our study, we conducted a case-control study in a northern Chinese Han population of 499 schizophrenia patients and 500 controls to investigate the effect of variant genotypes of 13 SNPs in ANK3 on schizophrenia risk. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using the chi-squared test, genetic model analysis, and haplotype analysis. Four ANK3 SNPs were associated with schizophrenia risk. The minor allele of rs958852 in ANK3 was associated with a 0.75-fold reduction in schizophrenia risk in an allelic model. In the genetic model, rs958852 was associated with a reduced schizophrenia risk, and rs10994336, rs10994338 and rs4948418 were associated with an increased schizophrenia risk (rs10994336, OR = 2.00, 95%CI: 1.01–3.94, p = 0.047; rs10994338, OR = 1.99, 95%CI: 1.01–3.93, p = 0.047; rs4948418, OR = 2.00, 95%CI: 1.01–3.94, p = 0.047). In addition, haplotype “TTC” of ANK3 was associated with a 0.73-fold reduced schizophrenia risk (95%CI: 0.54–0.99; p = 0.044). To our knowledge, this is the first to report of an association between ANK3 rs10994336, rs10994338, rs4948418 and rs958852 and schizophrenia risk in a northern Chinese Han population.

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          Most cited references 36

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          Biological Insights From 108 Schizophrenia-Associated Genetic Loci

          Summary Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here, we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain providing biological plausibility for the findings. Many findings have the potential to provide entirely novel insights into aetiology, but associations at DRD2 and multiple genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that play important roles in immunity, providing support for the hypothesized link between the immune system and schizophrenia.
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            Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010.

            We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) to estimate the burden of disease attributable to mental and substance use disorders in terms of disability-adjusted life years (DALYs), years of life lost to premature mortality (YLLs), and years lived with disability (YLDs). For each of the 20 mental and substance use disorders included in GBD 2010, we systematically reviewed epidemiological data and used a Bayesian meta-regression tool, DisMod-MR, to model prevalence by age, sex, country, region, and year. We obtained disability weights from representative community surveys and an internet-based survey to calculate YLDs. We calculated premature mortality as YLLs from cause of death estimates for 1980-2010 for 20 age groups, both sexes, and 187 countries. We derived DALYs from the sum of YLDs and YLLs. We adjusted burden estimates for comorbidity and present them with 95% uncertainty intervals. In 2010, mental and substance use disorders accounted for 183·9 million DALYs (95% UI 153·5 million-216·7 million), or 7·4% (6·2-8·6) of all DALYs worldwide. Such disorders accounted for 8·6 million YLLs (6·5 million-12·1 million; 0·5% [0·4-0·7] of all YLLs) and 175·3 million YLDs (144·5 million-207·8 million; 22·9% [18·6-27·2] of all YLDs). Mental and substance use disorders were the leading cause of YLDs worldwide. Depressive disorders accounted for 40·5% (31·7-49·2) of DALYs caused by mental and substance use disorders, with anxiety disorders accounting for 14·6% (11·2-18·4), illicit drug use disorders for 10·9% (8·9-13·2), alcohol use disorders for 9·6% (7·7-11·8), schizophrenia for 7·4% (5·0-9·8), bipolar disorder for 7·0% (4·4-10·3), pervasive developmental disorders for 4·2% (3·2-5·3), childhood behavioural disorders for 3·4% (2·2-4·7), and eating disorders for 1·2% (0·9-1·5). DALYs varied by age and sex, with the highest proportion of total DALYs occurring in people aged 10-29 years. The burden of mental and substance use disorders increased by 37·6% between 1990 and 2010, which for most disorders was driven by population growth and ageing. Despite the apparently small contribution of YLLs--with deaths in people with mental disorders coded to the physical cause of death and suicide coded to the category of injuries under self-harm--our findings show the striking and growing challenge that these disorders pose for health systems in developed and developing regions. In view of the magnitude of their contribution, improvement in population health is only possible if countries make the prevention and treatment of mental and substance use disorders a public health priority. Queensland Department of Health, National Health and Medical Research Council of Australia, National Drug and Alcohol Research Centre-University of New South Wales, Bill & Melinda Gates Foundation, University of Toronto, Technische Universität, Ontario Ministry of Health and Long Term Care, and the US National Institute of Alcohol Abuse and Alcoholism. Copyright © 2013 Elsevier Ltd. All rights reserved.
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              Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.

              The relative effectiveness of second-generation (atypical) antipsychotic drugs as compared with that of older agents has been incompletely addressed, though newer agents are currently used far more commonly. We compared a first-generation antipsychotic, perphenazine, with several newer drugs in a double-blind study. A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the Food and Drug Administration. The primary aim was to delineate differences in the overall effectiveness of these five treatments. Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001) or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group. The times to discontinuation because of intolerable side effects were similar among the groups, but the rates differed (P=0.04); olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects. The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons. Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism. Copyright 2005 Massachusetts Medical Society.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                27 December 2016
                3 November 2016
                : 7
                : 52
                : 85888-85894
                Affiliations
                1 Xi'an Mental Health Center, Xi’an, Shaanxi 710061, China
                2 Inner Mongolia Medical University Hohhot 010010, Inner Mongolia, China
                3 School of Life Sciences, Northwest University, Xi’an 710069, China
                4 Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China
                5 Key Laboratory of High Altitude Environment and Genes Related to Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China
                6 Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi 712082, China
                Author notes
                Correspondence to: Xianyang Liu, liuxianyang2016@ 123456126.com
                Article
                13043
                10.18632/oncotarget.13043
                5349882
                27811378
                Copyright: © 2016 Guo et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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